The proposed research program combines three research topics: 1) development and application of methods for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI) toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral lithium reagents for asymmetric alkylation reactions wih dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of dragmacidin D and a several members of C30-sesquiterpenoid Nuphar thioalkaloids that display an array of biological activity associated with the inhibition of NFkB-regulated pathways. In the third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution and unknown human health risks. We will carry out comprehensive functional studies on the interaction of CI toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model. In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and broader impact of nAChRs on neurodegenerative disorders.
Complex molecules derived from nature continue to be important lead compounds for drug development in many therapeutic areas, especially in cancer, infectious diseases, and neurological disorders. Our goals are the development of methods and strategies to enable rapid and economical access to such compounds. Another specific goal is to use a novel class of marine toxins as probes to study the biology associated with nicotinic acetylcholine receptors and their effect on cholinergic signal transmission, which i implicated in a number of physiologically important processes.
|Stivala, Craig E; Benoit, Evelyne; Aráoz, Rómulo et al. (2015) Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins. Nat Prod Rep 32:411-35|
|Xiao, Qing; Young, Kyle; Zakarian, Armen (2013) An efficient synthesis of the fully elaborated isoindolinone unit of muironolide A. Org Lett 15:3314-7|
|Lu, Ping; Gu, Zhenhua; Zakarian, Armen (2013) Total synthesis of maoecrystal V: early-stage C-H functionalization and lactone assembly by radical cyclization. J Am Chem Soc 135:14552-5|
|Xiao, Qing; Jackson, Jeffrey J; Basak, Ashok et al. (2013) Enantioselective synthesis of tatanans A-C and reinvestigation of their glucokinase-activating properties. Nat Chem 5:410-6|
|Hess, Philipp; Abadie, Eric; Hervé, Fabienne et al. (2013) Pinnatoxin G is responsible for atypical toxicity in mussels (Mytilus galloprovincialis) and clams (Venerupis decussata) from Ingril, a French Mediterranean lagoon. Toxicon 75:16-26|
|Herrmann, Aaron T; Smith, Lindsay L; Zakarian, Armen (2012) A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates. J Am Chem Soc 134:6976-9|
|Stivala, Craig E; Gu, Zhenhua; Smith, Lindsay L et al. (2012) Studies toward the synthesis of spirolide C: exploration into the formation of the 23-membered all-carbon macrocyclic framework. Org Lett 14:804-7|
|Herrmann, Aaron T; Martinez, Steven R; Zakarian, Armen (2011) A concise asymmetric total synthesis of (+)-brevisamide. Org Lett 13:3636-9|
|Araoz, Romulo; Servent, Denis; Molgo, Jordi et al. (2011) Total synthesis of pinnatoxins A and G and revision of the mode of action of pinnatoxin A. J Am Chem Soc 133:10499-511|
|Gu, Zhenhua; Zakarian, Armen (2011) Studies toward the synthesis of maoecrystal V. Org Lett 13:1080-2|
Showing the most recent 10 out of 15 publications